Phase III NALA Trial Meets Primary Endpoint in Previously Treated HER2-Positive Breast Cancer

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As reported in the Journal of Clinical Oncology by Cristina Saura, MD, of Vall d’Hebron University Hospital, Barcelona, and colleagues, the phase III NALA trial has shown significantly prolonged progression-free survival with the irreversible pan-HER tyrosine kinase inhibitor neratinib plus capecitabine vs the reversible dual tyrosine kinase inhibitor lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer who had received at least two prior HER2-directed regimens.1 No significant improvement in overall survival, a co-primary endpoint, was observed.

The trial supported the February 2020 approval of neratinib in combination with capecitabine for treatment of adults with advanced or metastatic HER2-positive breast cancer who have received two or more prior anti–HER2-based regimens in the metastatic setting.

Cristina Saura, MD

Cristina Saura, MD

Study Details

In the open-label trial, 621 patients (including 3 men) from 28 countries in Europe, North and South America, Asia, and Australia were randomly assigned between May 2013 and July 2017 to receive neratinib plus capecitabine (n = 307) or lapatinib plus capecitabine (n = 314). Patients with stable, asymptomatic central nervous system (CNS) disease were eligible for the study. Randomization was stratified by hormone receptor status, number of previous HER2-directed therapies for metastatic disease, geographic region (North America or Europe or the rest of the world), and presence or absence of visceral disease.

The neratinib group received neratinib at 240 mg once daily plus capecitabine at 750 mg/m2 twice daily on days 1 to 14 of 21-day cycles, with mandated loperamide antidiarrheal prophylaxis during cycle 1. The lapatinib group received the agent at 1,250 mg once daily plus capecitabine at 1,000 mg/m2 twice daily on days 1 to 14 of 21-day cycles. Treatment was continued until disease progression or unacceptable toxicity. The co-primary endpoints were progression-free survival upon blinded central review and overall survival.

Efficacy Outcomes

Median follow-up was 29.9 months (interquartile range = 21.9–40.6 months). The neratinib group had significantly prolonged progression-free survival vs the lapatinib group (hazard ratio [HR] = 0.76, 95% confidence interval [CI] = 0.63–0.93; P = .0059). Median progression-free survival was 5.6 months (95% CI = 4.9–6.9 months) vs 5.5 months (95% CI = 4.3–5.6 months). The Kaplan-Meier curves for progression-free survival overlapped during the first 24 weeks of treatment and thereafter showed clear separation; the shape of the curve indicated violation of the proportional hazard assumption, which was confirmed by statistical testing. A restricted means analysis supported the primary analysis, showing mean progression-free survival of 8.8 months (95% CI = 7.8–9.8 months) vs 6.6 months (95% CI = 5.9–7.4 months; P = .0003), with a mean difference of 2.2 months. Kaplan-Meier estimates of progression-free survival at 6, 12, and 18 months were 47.2% vs 37.8%, 28.8% vs 14.8%, and 16.3% vs 7.4%, respectively.

Hazard ratios for progression-free survival favored neratinib/capecitabine for most prespecified subgroup analyses. A significant interaction (P < .05) was observed for hormone receptor status and disease location. Hazard ratios were 0.42 (95% CI = 0.31–0.57) among patients with hormone receptor–negative disease and 1.08 (95% CI = 0.84–1.40) among those with hormone receptor–positive disease. Hazard ratios were 0.85 (95% CI = 0.69–1.04) among patients with visceral disease and 0.44 (95% CI = 0.26–0.73) for patients with nonvisceral disease alone.

A numeric benefit of neratinib/capecitabine in overall survival was observed (192 vs 218 deaths) but did not achieve statistical significance (HR = 0.88, 95% CI = 0.72–1.07, P = .2086). Mean overall survival was 24.0 months (95% CI = 22.1–25.9 months) vs 22.2 months (95% CI = 20.4–24.0 months).

The overall cumulative incidence of intervention for CNS disease was 22.8% vs 29.2% (P = .043). Objective response was observed in 32.8% of 256 patients in the neratinib group vs 26.7% of 270 patients in the lapatinib group, with measurable disease at baseline (P = .120), including a complete response in 4 patients (1.6%) vs 1 patient (0.4%). The median duration of response was 8.5 months vs 5.6 months (HR = 0.50, P = .0004). The proportion of patients with responses lasting at least 12 months was 36.9% vs 16.8%. The clinical benefit rate was 44.5% vs 35.6% (P = .0328).

Adverse Events

The most common adverse events of any grade in the neratinib group vs the lapatinib group were diarrhea (83% vs 66%), nausea (53% vs 42%), palmar-plantar erythrodysesthesia (45.9% vs 56.3%), and vomiting (45.5% vs 31.2%). Grade 3 or 4 adverse events occurred in 58% vs 57% of patients, with the most common in the neratinib group including diarrhea (24.4% vs 12.5%; all grade 3), palmar-plantar erythrodysesthesia (9.6% vs 11.3%), hypokalemia (4.6% vs 6.4%), nausea (4.3% vs 2.9%), and vomiting (4.0% vs 1.9%). Grade 3 diarrhea was most
common during cycle 1 of treatment (16% vs 5%).

Serious adverse events occurred in 34.0% vs 29.9% of patients. Adverse events led to discontinuation of any study drug in 13.9% vs 18.0%. Adverse events led to death in 8 patients in the neratinib group and in 10 patients in the lapatinib group.

No new safety concerns regarding cardiac events were identified. Cardiac arrhythmia occurred in 3.3% vs 3.5% of patients; ischemic heart disease, in 0.7% vs 0.6%; QT prolongation, in 2.3% vs 3.9%; and left-ventricular ejection fraction decrease, in 4.3% vs 2.3%.

The investigators concluded: “NALA is the first study to demonstrate superiority of one HER2-directed tyrosine kinase inhibitor over another in metastatic breast cancer and provides evidence for the efficacy and tolerability of [neratinib plus capecitabine] in this setting. The primary endpoint of centrally assessed [progression-free survival] was significantly improved with [neratinib plus capecitabine] vs [lapatinib vs capecitabine], and there were favorable outcomes across secondary endpoints, including [duration of response] and time to intervention for CNS disease. [Neratinib plus capecitabine] is an appropriate treatment option for patients with HER2-positive metastatic breast cancer progressing after at least two lines of HER2-directed treatment.” 

DISCLOSURE: The study was supported by Puma Biotechnology. For full disclosures of the study authors, visit


1. Saura C, Oliveira M, Feng YH, et al: Neratinib plus capecitabine vs lapatinib plus capecitabine in HER2-positive metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: Phase III NALA Trial. J Clin Oncol 38:3138-3149, 2020.